The present invention relates to the treatment and prevention of excessive scarring, including keloid and hypertrophic scars, with 4-hydroxy tamoxifen (4-OHT).
Keloid scars, or keloids, are overgrowths of dense fibrous tissue that result from variations in normal wound healing. The dense fibrous tissue of a keloid extends beyond the borders of the original wound, and usually does not regress spontaneously. Thus, keloid scarring is out of proportion to the severity of the inciting wound.
Likewise, hypertrophic scars also are overgrowths of dense fibrous tissue that result from abnormal wound healing. However, hypertrophic scars do not extend beyond the original boundaries of a wound. Also unlike keloids, hypertrophic scars reach a certain size, then stabilize or regress.
The normal wound healing process extends over a one to two year period, and conceptually consists of three distinct stages. The first stage, the inflammatory stage, is intensely degradative. It begins immediately after injury and provides a means to remove damaged tissues and foreign matter from the wound. A few days after injury, the second stage, the proliferation and matrix synthesis stage, begins. During this stage, fibroblasts from surrounding tissues move into the wound and proliferate. The fibroblasts actively produce collagen, which they secrete into the extracellular matrix. Newly synthesized collagen forms cross-linked fibrils, which provide structural integrity to the wound. After several weeks, the final stage, the remodeling stage, begins. During the remodeling stage, the collagen fibrils, which previously were randomly oriented, align in the direction of mechanical tension, providing further mechanical strength to the wound. Upon completion of the entire process, the skin regains its chemical and physical barrier functions.
Six to eight weeks into the normal wound healing process, anabolic and catabolic processes reach an equilibrium. At this time, scar strength is approximately 30-40% that of healthy skin, and scars typically are hyperemic and thickened. Over the next several months, catabolic and anabolic processes abate, and progressive cross-linking of collagen fibers improves the wound's tensile strength. Also, hyperemia and thickness subside until a flat, white, pliable mature scar develops.
Excessive scarring results from an imbalance in the anabolic and catabolic wound healing processes. In the formation of an excessive scar, more collagen is produced than is degraded. As a result, the scar grows larger than is required for wound healing, with an over-production of cells, collagen and proteoglycan. Keloids grow in all directions, become elevated above the skin, and remain hyperemic. The exact mechanisms of excessive scarring are poorly understood, but it is believed that common mechanisms underlie the formation of both keloids and hypertrophic scars. Evidence suggests that increased transforming growth factor β1 (TGF-β1) expression plays a role in excessive scarring. TGF-β1 promotes extracellular matrix production, and is produced at elevated levels by keloid fibroblasts.
Keloids and hypertrophic scars primarily present a cosmetic concern but can cause contractures, which may result in a loss of function if overlying a joint. Additionally, excessive scars can be painful, pruritic and cause a burning sensation. Once keloid lesions occur, they tend to continue growing for weeks to months, even for years. Growth usually progresses slowly, but keloids occasionally enlarge rapidly, even tripling in size within months. Hypertrophic scars tend to stabilize, and regress over time. However, this regression can be quite slow, and often incomplete.
Management of keloids and hypertrophic scars remains a major unsolved clinical problem. Though many forms of treatment have been used, none has proven to be consistently reliable. Current forms of treatment include use of occlusive dressings, compression therapy, intralesional corticosteroid injections, radiation therapy, and surgery.
Occlusive dressings and pressure devices are unpredictable forms of treatment, as a large percentage of patients treated by these means show little or no improvement. Additionally, compliance with these forms of treatment can be impractical. For example, dressings and pressure devices may need to be worn 24 hours per day for up to 12 months. For a scar on a visible or sensitive location, this simply may not be possible.
Intralesional corticosteroids have been the mainstay of keloid treatment. Corticosteroids reduce excessive scarring by reducing collagen synthesis, altering glucosaminoglycan synthesis, and reducing production of inflammatory mediators and fibroblast proliferation during wound healing. However, roughly half of all keloids fail to respond to corticosteroids, and roughly half of the scars that are completely resolved by corticosteroid treatment recur. Additionally, corticosteroid injections can cause several complications, including atrophy, telangiectasia formation, and skin depigmentation.
Radiation therapy may be the only predictably effective treatment for keloids that is presently available. It has the potential to cause cancer, however, and for this reason it is not generally recommended or accepted as a keloid treatment. Moreover, roughly 20 percent of keloids treated by radiation therapy alone recur within one year.
Surgical procedures, including excision, cryosurgery and laser therapy, can effectively remove keloid tissue, and currently are the treatment of choice for hypertrophic scars. However, these techniques often cause tissue trauma that results in further hypertrophic or keloid scars. Indeed, keloids recur in well more than half of patients treated by surgical excision, cryosurgery, and laser therapy. Additionally, these procedures cause pain and present a risk of infection. Cryosurgery also causes skin depigmentation in some patients.
As an alternative keloid treatment, some researchers have proposed using the breast cancer drug tamoxifen (Hu, 1998; Hu 2002). In vitro, tamoxifen inhibits keloid fibroblast proliferation and decreases collagen production. Apparently, tamoxifen effects this inhibition by downregulating TGF-β1 expression, which promotes collagen formation (Chau 1998; Mikulec, 2001).
In vivo use of tamoxifen for treating scars would have drawbacks, however. Tamoxifen is currently available only for oral administration, and its administration by this route poses serious health risks and causes significant unwanted side effects. Tamoxifen potentially impacts on every estrogen receptor in the body, and, as both an agonist and antagonist, provokes a wide range of systemic effects. These effects include the increased risk of endometrial cancer, endometrial hyperplasia and polyps, deep vein thrombosis and pulmonary embolism, changes in liver enzyme levels, and ocular disturbances, including cataracts. Additionally, patients treated with oral tamoxifen reported having hot flashes, vaginal discharge, depression, amenorrhea, and nausea (Fentiman 1986; Fentiman 1988; Fentiman 1989; Ibis 2002). Locally administered tamoxifen, which might pose fewer risks, would eliminate first-pass liver metabolism, which changes tamoxifen into its active metabolites. Without liver metabolism, tamoxifen would be less effective.
Thus, despite the broad array of treatments available, there is no widely accepted and predictably effective means for preventing or treating excessive scars. Therefore, an effective approach to reducing keloid and hypertrophic scars would offer significant benefit if it also provoked few systemic side effects.